Taltz ® (ixekizumab) injektion

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Taltz®▼ (ixekizumab): Hur verkar ixekizumab jämfört med adalimumab vid psoriasisartrit?

I en jämförande studie visade sig ixekizumab vara effektivare än adalimumab för att simultant nå de primära effektmåtten för ACR50 och PASI 100.

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Taltz® (ixekizumab): Comparison With Adalimumab for Psoriatic Arthritis

Summary

  • Efficacy and safety of Ixekizumab was investigated in a multicenter, randomized, open-label, rater-blinded, parallel-group study (SPIRIT-H2H) compared to adalimumab in 566 patients with PsA who were naïve to biologic disease-modifying anti-rheumatic drugs (bDMARD). Patients were stratified at baseline based on concomitant cDMARD use and presence of moderate-to-severe psoriasis (PASI≥12, BSA≥10 and sPGA≥3).1

  • In SPIRIT-H2H, ixekizumab was superior to adalimumab at the primary endpoint, which was simultaneous achievement of both ACR50 and PASI 100 at week 24. Additionally, all key secondary endpoints were met.2 These results were maintained through week 52.3

  • The efficacy of ixekizumab was sustained over 52 weeks regardless of whether it was taken as monotherapy or in combination with csDMARDS. Results from the subset of patients taking MTX at baseline were consistent with those of the broader csDMARD group. Adalimumab was associated with numerically lower response rates when used as monotherapy rather than in combination with csDMARDs.3,4

  • In SPIRIT-H2H, the safety profiles of ixekizumab and adalimumab were consistent with previously reported results and approved label information.2

Ixekizumab for Treatment of Psoriatic Arthritis

SPIRIT-H2H Study Design

Design and Dosing Arms

SPIRIT-H2H (N=566) is a 52-week randomized, open-label, parallel-group, phase 3b/4 clinical trial with blinded assessor to evaluate the efficacy and safety of ixekizumab with that of adalimumab in patients with active PsA (≥3 TJC and ≥3 SJC) and plaque PsO (BSA ≥3%) at baseline who are bDMARD-naive. The blinded assessors were not allowed to know the patient's treatment allocation or to be otherwise involved in the study procedures. To be qualified as a blinded assessor, a minimum of 1-year of experience using the instrument tools was required.5

For patients randomized to ixekizumab who met the study’s definition of moderate-to-severe PsO, ixekizumab was administered 80 mg Q2W from week 2 to 12 after a 160 mg starting dose at week 0, and Q4W thereafter. For all other patients randomized to ixekizumab, dosing was ixekizumab 80 mg Q4W after a 160 mg starting dose at week 0.2 Please refer to Taltz summary of product characteristics for full dosing information.1

For patients randomized to adalimumab who met the study’s definition of moderate-to-severe PsO, adalimumab was administered 80 mg at week 0, followed by 40 mg Q2W starting at week 1. For all other patients randomized to adalimumab, dosing was adalimumab 40 mg Q2W.2

Randomization was stratified by concomitant cDMARD use at baseline and moderate-to-severe plaque PsO involvement at baseline (defined in this study as meeting all 3 criteria: PASI ≥12, sPGA ≥3, and BSA ≥10%).2

Outcome Measures

The primary outcome of SPIRIT-H2H was the proportion of patients simultaneously achieving both ACR50 and PASI 100 at week 24. This outcome was controlled for type-1 error.2

The 2 major secondary endpoints at week 24 were

  • ACR50 (noninferiority to adalimumab), and

  • PASI 100 (superiority to adalimumab).2

The above endpoints were also controlled for type-1 error.2

Additional secondary endpoints (not controlled for type-1 error) included 

  • proportion of patients achieving ACR20 and ACR70 responses

  • proportion of patients who achieve PASI 75 or PASI 90 scores

  • composite measures incorporating multiple disease domains in PsA (MDA, DAPSA [post hoc analysis], or PASDAS [post hoc analysis])

  • resolution of enthesitis (SPARCC or LEI)

  • resolution of dactylitis (LDI-B), and

  • quality of life endpoints (SF-36, HAQ-DI and DLQI).2,6

Patient Population

Enrolled patients (N=566) had active PsA (defined as the presence of at least 3 tender and at least 3 swollen joints) and plaque psoriasis with BSA ≥3%, had an inadequate response to at least one cDMARD, and were bDMARD naive.2

After week 24 database lock and initial analysis run, a medical inconsistency in baseline PASI data was identified. Although 9 patients were assessed as PASI=0 at baseline, those patients fulfilled the criteria for having psoriasis as assessed by a BSA ≥3%. Therefore, these patients were judged as PASI 100 responders if they achieved an absolute PASI=0 and BSA=0 at post baseline visits. Multiple analyses to assess the robustness of this approach were conducted.2

Of the 283 patients randomized to each treatment arm, 269 (95%) patients in the adalimumab arm and 262 (93%) patients in the ixekizumab arm completed the week 24 study visit, and 237 (84%) patients in the adalimumab arm and 246 (87%) patients in the ixekizumab arm completed the week 52 study visit.2,3,7

Baseline demographics and disease characteristics for patients enrolled in SPIRIT-H2H are presented in  . Patients were stratified by cDMARD use and presence of moderate-to-severe psoriasis.2

Table 1. SPIRIT-H2H: Baseline Patient Demographics and Disease Characteristics, ITT Population2

 

ADA
N=283

IXE
N=283

Age, years

48.3±12

47.5±12

Female, n (%)

133 (47)

121 (43)

PsA duration since diagnosis, years

5.9±6

6.6±7

PsO duration since diagnosis, years

14.7±13

16.1±13

Concomitant cDMARD use, n (%)

199 (70)

193 (68)

Concomitant methotrexate use, n (%)

169 (60)

167 (59)

Tender joint count

21.3±15

19.1±13

Swollen joint count

10.7±8

10.1±7.5

SPARCC enthesitis index >0, n (%)

171 (60)

189 (67)

LEI >0, n (%)

147 (52)

159 (56)

LDI-B >0, n (%)

58 (21)

42 (15)

Moderate-to-severe PsO, n (%)a

51 (18)

49 (17)

PASI

7.7±7

7.9±9

Abbreviations: ADA = adalimumab; BSA = body surface area; cDMARD = conventional disease-modifying antirheumatic drug; ITT = intent-to-treat; IXE = ixekizumab; LDI-B = Leeds Dactylitis Index-Basic; LEI = Leeds Enthesitis Index; PASI = Psoriasis Area and Severity Index; PsA = psoriatic arthritis; PsO = psoriasis; SD = standard deviation; SPARCC = Spondyloarthritis Research Consortium of Canada; sPGA = static Physician Global Assessment.

Values are mean ± SD unless otherwise noted.

a Criteria for moderate-to-severe psoriasis were PASI ≥12, sPGA ≥3, and BSA ≥10%.

SPIRIT-H2H Efficacy Results

Primary Outcome: Simultaneous Achievement of ACR50 and PASI 100 at Week 24

Ixekizumab showed superior efficacy to adalimumab based on the primary outcome of the SPIRIT-H2H trial, simultaneous achievement of ACR50 and PASI 100 responses at week 24. As shown in Figure 1, significant differences in achieving simultaneous ACR50 and PASI 100 responses were observed as early as week 8 and continued through week 52.2,3

Figure 1. Percentage of Patients who Achieved Simultaneous ACR50 and PASI 100 in SPIRIT-H2H Through 52 Weeks by Treatment Week, NRI7

Abbreviations: ACR50 = 50% improvement from baseline in American College of Rheumatology Index; ADA = adalimumab; IXE = ixekizumab; NRI = nonresponder imputation; PASI 100 = 100% improvement from baseline in Psoriasis Area and Severity Index; W24 = week 24; W52 = week 52.

*p<.01 vs ADA.
† p<.05 vs ADA.
‡ p<.001 vs ADA.

Major Secondary Endpoints: Achievement of ACR50 and PASI 100 at Week 24

As measured by ACR50, ixekizumab was noninferior to adalimumab (noninferiority margin, -12.0%) with no statistically significant differences in ACR50 response between the treatment arms through week 52 (see Figure 2).2,3

Figure 2. Percentage of Patients who Achieved ACR50 in SPIRIT-H2H Through 52 Weeks by Treatment Week, NRI 7

Abbreviations: ACR50 = 50% improvement from baseline in American College of Rheumatology Index; ADA = adalimumab; IXE = ixekizumab; NRI = nonresponder imputation; W24 = week 24; W52 = week 52.

The PASI 100 response was significantly greater in the ixekizumab treatment than in the adalimumab arm with statistically significant differences observed at the first PASI assessment at week 4 and every assessment through week 52 (see Figure 3).2,3

Figure 3. Percentage of Patients who Achieved PASI 100 Response in SPIRIT-H2H Through 52 Weeks by Treatment Week, NRI7

Abbreviations: ADA = adalimumab; IXE = ixekizumab; NRI = nonresponder imputation; PASI 100 = 100% improvement from baseline in Psoriasis Area and Severity Index; W24 = week 24; W52 = week 52.

*p≤.001 vs ADA.

Additional Secondary Outcomes

Additional secondary outcomes at weeks 24 and 52 are provided in  . Greater improvements with ixekizumab than with adalimumab at week 24 were attained in

  • enthesitis resolution (via SPARCC and LEI)

  • composite outcomes (MDA, VLDA, DAPSA remission [score ≤4], and PASDAS near remission [score ≤1.9]), and

  • psoriasis skin assessments (PASI 75 and PASI 90).2,7

Responses were comparable between the treatment arms for ACR20, ACR70, and dactylitis resolution (via LDI-B) at week 24.2,7

At week 52, patients in the ixekizumab group had significantly higher response rates than the adalimumab group for PASI 75 (p=.008) and PASI 90 (≤.001) (see  ).3

While the rate of nail psoriasis resolution was similar between groups at week 52, patients in the ixekizumab group had significantly greater improvement from baseline in NAPSI scores than did the adalimumab group (ixekizumab, -17.78; adalimumab, -15.08; p=.005).3

Compared with adalimumab, patients who received ixekizumab had significantly greater improvements from baseline in mCPDAI at week 52 (ixekizumab, -4.35; adalimumab, -3.85; p=.004). Significant differences were observed as early at the first postbaseline assessment at week 12.3

 

Table 2. SPIRIT-H2H: Secondary Efficacy Outcomes at Weeks 24 and 52, NRI2,3,6,7

Efficacy Outcome, %

Week 24

Week 52

IXE (N=283)

ADA (N=283)

IXE (N=283)

ADA (N=283)

ACR20

69

72

70

69

ACR70

32

26

35

34

PASI 75

80a

69

78b

69

PASI 90

72c

56

73c

54

MDAd

48e

35

47

41

VLDAd

17e

10

23

19

DAPSA ≤4

27e

18

30

28

PASDAS near remission (≤1.9)

29a

19

---

---

LEI=0

60

55

62

57

SPARCC enthesitis index=0f

57e

45

57

49

LDI-basic=0g

88

93

83

81

NAPSI fingernails=0

58

50

68

59

Abbreviations: ACR20/70 = 20%/70% improvement from baseline in American College of Rheumatology criteria; ADA = adalimumab; BSA = body surface area; DAPSA = Disease Activity for Psoriatic Arthritis; HAQ-DI = Health Assessment Questionnaire-Disability Index; IXE = ixekizumab; LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MDA = minimal disease activity; NAPSI = Nail Psoriasis Severity Index; NRI = nonresponder imputation; PASDAS = Psoriatic Arthritis Disease Activity Score; PASI = Psoriasis Area and Severity Index; PASI 75/90 = 75%/90% improvement from baseline in Psoriasis Area Severity Index score; PatGA = Patient's Global Assessment; SJC = swollen joint count; SPARCC = Spondyloarthritis Research Consortium of Canada; TJC = tender joint count; VAS = Visual Analog Scale; VLDA = very low disease activity.

a p<.01 vs ADA.

b p=.008 vs ADA.

c p≤.001 vs ADA.

d Patients were classified as achieving MDA if they fulfilled 5 of 7 of the MDA component (TJC ≤1; SJC ≤1; PASI total score ≤1 or BSA ≤3; patient pain VAS score ≤15; PatGA VAS score ≤20; HAQ-DI score ≤0.5; and tender entheseal points ≤1). Patients were classified as VLDA if they fulfilled 7 of 7 of the MDA components.

e p<.05 vs ADA.

f There were 189 IXE and 171 ADA treated patients with SPARCC enthesitis index scores >0 at baseline.

g There were 42 IXE and 58 ADA treated patients with LDI scores >0 at baseline.

Patient-Reported Quality of Life Outcomes at Week 24

Week 24

Patient reported quality of life endpoints at week 24 are provided in Table 3. Responses were similar between ixekizumab and adalimumab treatment groups for HAQ-DI and SF-36 component summaries. Change from baseline in DLQI was significantly better with ixekizumab treatment compared to adalimumab at week 24 (p<.001).6

Table 3. SPIRIT-H2H: Change From Baseline at Week 24 in Patient-Reported Quality of Life Outcomes, MMRM6

Outcome

24 Weeks

IXE

ADA

HAQ-DIa

-0.63

-0.56

DLQIb

-7.81c

-6.48

SF-36d

PCSe

10.0

8.8

MCSf

4.5

3.9

Abbreviations: ADA = adalimumab; DLQI = Dermatology Life Quality Index; HAQ-DI = Health Assessment Questionnaire–Disability Index; IXE = ixekizumab; MCID = Minimum Clinically Important Difference; MCS = Mental Component Summary; MMRM = Mixed-Effects Model for Repeated Measures; PCS = Physical Component Summary; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey.

a Baseline scores: IXE = 1.2, ADA =1.3.

b Baseline scores: IXE = 9.8, ADA = 9.8.

c p<.001 vs adalimumab.

d The MCID for SF-36 PCS and MCS scores is an improvement from baseline of 2.5.

e Baseline scores: IXE = 37, ADA = 36.

f Baseline scores: IXE = 45, ADA = 45.

Week 52

Patient-reported quality of endpoints at week 52 are provided in Table 4. Responses were similar between ixekizumab and adalimumab for the proportion of patients who achieved MCID for HAQ-DI and change from baseline in SF-36 PCS. Compared with the adalimumab group, patients in the ixekizumab group had significantly greater improvements in skin-related quality of life as measured by DLQI (0,1) at week 52 (p=.014), with significant differences observed as early as week 4.3

Table 4. SPIRIT-H2H: Change From Baseline at Week 52 in Patient-Reported Quality of Life Outcomes3

Outcome

52 Weeks

IXE

ADA

HAQ-DI improvement by ≥0.35, %a

66.7

64.6

DLQI (0-1), %

59.0b

48.8

SF-36 PCS change from baseline

10.1

9.6

Abbreviations: ADA = adalimumab; DLQI = Dermatology Life Quality Index; HAQ-DI = Health Assessment Questionnaire-Disability Index; IXE = ixekizumab; PCS = Physical Component Summary; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey.

a Assessed for patients with HAQ-DI score ≥0.35 at baseline.

b p=.014 vs ADA.

Efficacy in Patient Subgroups at Week 24

A post hoc analysis compared ACR20, ACR50, ACR70, and MDA (6 entheseal points) results at week 24 between the ixekizumab and adalimumab groups by baseline

  • presence (LEI >0 or SPARCC >0) or absence (LEI =0 or SPARCC =0) of enthesitis

  • presence (LDI-B >0) or absence (LDI-B =0) of dactylitis

  • presence (NAPSI >0) or absence (NAPSI =0) of fingernail psoriasis

  • BSA with 10% cutoff, and

  • CRP with 6 mg/L cutoff.8

The ACR20 and ACR50 response rates were not statistically significantly different between the ixekizumab and adalimumab groups for any of the evaluated baseline characteristics.8

The ACR70 response rates were comparable between treatment groups for each of the evaluated baseline characteristics with the exception of baseline fingernail psoriasis. Compared with adalimumab, significantly more patients with fingernail psoriasis at baseline who received ixekizumab achieved ACR70 at week 24 (p<.05).8

The percentages of patients who achieved MDA (6 entheseal points) was significantly greater in the ixekizumab group than in the adalimumab group in subgroups of patients

  • with enthesitis (p<.01)

  • without dactylitis (p<.05)

  • with fingernail psoriasis (p<.001)

  • with CRP ≤6 mg/L (p<.05), and

  • with BSA ≥10% (p<.01) (see Table 5).8

The percentages of patients who achieved MDA (6 entheseal points) was similar among the ixekizumab and adalimumab groups for the other evaluated subgroups.8

Table 5. SPIRIT-H2H: Percentage of Patients who Achieved Efficacy Outcomes at Week 24 by Patient Subgroup8

Outcome, %

ACR20

ACR50

ACR70

MDA-6a

IXE

ADA

IXE

ADA

IXE

ADA

IXE

ADA

Baseline Enthesitis

Present (IXE, N=193; ADA, N=172)b

67

66

47

42

30

21

45c

29

Absent (IXE, N=89; ADA, N=111) d

73

81

60

53

37

33

58

49

Baseline Dactylitis

Present (IXE, N=42; ADA, N=58)e

67

78

55

53

31

24

50

33

Absent (IXE, N=240; ADA, N=225)f

70

71

50

45

32

26

49g

38

Baseline Fingernail Psoriasis

Present (IXE, N=191; ADA, N=177)h

71

73

53

46

33g

22

50i

32

Absent (IXE, N=92; ADA, N=105)j

64

71

46

48

29

32

48

45

Baseline CRP Level

6 mg/L (IXE, N=167; ADA, N=167)

66

74

49

44

29

25

48g

37

>6 mg/L (IXE, N=109; ADA, N=109)

75

70

55

50

37

28

50

39

Baseline Plaque Psoriasis

BSA 3 to 10% (IXE, N=170; ADA, N=179)

64

72

46

45

29

24

45

36

BSA ≥10% (IXE, N=113; ADA, N=104)

76

73

57

50

36

29

56c

38

Abbreviations: ACR = American College of Rheumatology criteria; ADA = adalimumab; BSA = body surface area; CRP = C-reactive protein; HAQ-DI = Health Assessment Questionnaire-Disability Index; IXE = ixekizumab; LDI-B = Leeds Dactylitis Index-Basic; LEI = Leeds Enthesitis Index; MDA-6 = Minimal Disease Activity (6 entheseal points); NAPSI = Nail Psoriasis Severity Index; PASI = Psoriasis Area and Severity Index; SJC = swollen joint count; TJC = tender joint count; SPARCC = Spondyloarthritis Research Consortium of Canada; VAS = Visual Analog Scale.

a MDA (6 entheseal points) is the achievement of ≥5 of the following 7 criteria: TJC ≤1; SJC ≤1; pain VAS ≤15; patient’s global assessment ≤20; HAQ-DI ≤0.5; LEI ≤1; PASI ≤1 or BSA ≤3%.

b LEI >0 or SPARCC >0.

c p<.01 vs ADA.

d LEI=0 or SPARCC=0.

e LDI-B >0.

f LDI-B=0.

g p<.05 vs ADA.

h NAPSI >0.

i p<.001 vs ADA.

j NAPSI=0.

Efficacy by Baseline Severity of Psoriasis

A subgroup analysis of efficacy by presence or absence of moderate-to-severe psoriasis found that the efficacy of ixekizumab was not influenced by baseline psoriasis severity. Results of simultaneous achievement of ACR50 and PASI 100, ACR50 response rates, and PASI 100 response rates by presence or absence of moderate-to-severe psoriasis at baseline through week 52 are shown in Figure 4, Figure 5, and Figure 6.3

Figure 4. Simultaneous ACR50 and PASI 100 Response Rates Through Week 52 in SPIRIT-H2H by Baseline Psoriasis Severity3

Abbreviations: ACR50 = 50% improvement from baseline in American College of Rheumatology Index; ADA = adalimumab; IXE = ixekizumab; PASI 100 = 100% improvement from baseline in Psoriasis Area and Severity Index.

*p<.05 vs ADA.
† p<.01 vs ADA.

Figure 5. ACR50 Response Rates Through Week 52 in SPIRIT-H2H by Baseline Psoriasis Severity3

Abbreviations: ACR50 = 50% improvement from baseline in American College of Rheumatology Index; ADA = adalimumab; IXE = ixekizumab.

Figure 6. PASI 100 Response Rates Through Week 52 in SPIRIT-H2H by Baseline Psoriasis Severity3

Abbreviations: ADA = adalimumab; IXE = ixekizumab; PASI 100 = 100% improvement from baseline in Psoriasis Area and Severity Index.

*p<.05 vs ADA.
† p<.01 vs ADA.
‡ p<.001 vs ADA.

Efficacy by Baseline use of Methotrexate at Weeks 24 and 52

The percentage of patients who achieved the primary endpoint of simultaneous ACR50 and PASI 100 responses at week 24 was consistent in the ixekizumab group regardless of concomitant methotrexate use (see Table 6).7

Table 6. SPIRIT-H2H: Efficacy by Baseline use of Methotrexate7


Efficacy Outcome, %

Week 24

Week 52

IXE

ADA

IXE

ADA

MTX (N=167)

No MTXa (N=116)

MTX (N=169)

No MTXa (N=114)

MTX (N=167)

No MTXa (N=116)

MTX (N=169)

No MTXa (N=114)

Simultaneous ACR50 and PASI 100

40

31

31

23

39

40b

30

20

ACR20

70

67

75

68

68

72

75

60

ACR50

54

45

47

46

48

53

56

40

ACR70

34

29

27

25

32

41c

39

27

Abbreviations: ACR20/50/70 = 20%/50%/70% improvement from baseline in American College of Rheumatology criteria; ADA = adalimumab; IXE = ixekizumab; MTX = methotrexate; PASI 100 = 100% improvement from baseline in Psoriasis Area and Severity Index.

a Patients in the No MTX group may be using concomitant leflunomide, sulfasalazine, or cyclosporine.

b p<.01 vs ADA in concomitant MTX subgroup.

c p<.05 vs ADA in concomitant MTX subgroup.

Efficacy by Baseline use of Concomitant Conventional Synthetic Disease-Modifying Antirheumatic Drugs Through 52 Weeks

The efficacy of ixekizumab compared with that of adalimumab through 52 weeks was stratified by baseline concomitant use of csDMARDs. A separate analysis was conducted by concomitant use of methotrexate.4 The numbers of patients in each treatment arm receiving concomitant csDMARDs in SPIRIT-H2H is presented in Table 7.

Table 7. SPIRIT-H2H: Baseline use of Concomitant Conventional Disease-Modifying Antirheumatic Drugs, ITT Population3


ADA
N=283
n (%)

IXE
N=283
n (%)

Concomitant cDMARD

199 (70)

193 (68)

Concomitant MTX

169 (60)a

167 (59)b

Abbreviations: ADA = adalimumab; cDMARD = conventional disease-modifying antirheumatic drug; CYC = cyclosporine; ITT = intent-to-treat; IXE = ixekizumab; LEF = leflunomide; MTX = methotrexate; SSZ = sulfasalazine.

a Of the 169 patients receiving MTX, 12 (7.1%) were also taking SSZ, LEF, or CYC.

b Of the 167 patients receiving MTX, 15 (9.0%) were also receiving SSZ, LEF, or CYC.

The efficacy of ixekizumab was sustained over 52 weeks regardless of whether it was taken as monotherapy or in combination with csDMARDS. Adalimumab was associated with numerically lower response rates when used as monotherapy rather than in combination with csDMARDs. Results from the separate analysis of concomitant use of methotrexate were similar to those of the broader csDMARD group.3,4

Figure 7. Percentage of Patients Achieving Simultaneous ACR50 and PASI 100 Response, NRI4